Growth factors are signaling molecules which bind their cognate cell surface receptors initiating signaling cascades that stimulate a variety of cellular processes including growth, metabolism, survival, migration and differentiation. One of the key growth factor signaling pathways is the PI3K (Phosphoinositide 3 Kinase)/Akt/mTOR (Mechanistic Target of Rapamycin) pathway. Akt (also called Protein Kinase B, PKB) is a serine/threonine kinase that mediates growth factor signaling by phosphorylating multiple cellular targets. (Manning B D, Cantley L C. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun. 29; 129(7):1261-74.)
Impaired growth factor signaling can lead to various disease conditions including skeletal muscle loss, hearing loss, degeneration of a number of organ systems and delayed wound healing. (Rüegg M A, Glass D J. Molecular mechanisms and treatment options for muscle wasting diseases. Annu Rev Pharmacol Toxicol. 2011; 51:373-95; Yamamoto N, Nakagawa T, Ito J. Application of insulin-like growth factor-1 in the treatment of inner ear disorders. Front Pharmacol. 2014 Sep. 10; 5:208; Böhm F, Kohler U A, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med. 2010 August; 2(8):294-305; Sádaba M C, Martin-Estal I, Puche J E, Castilla-Cortázar I. Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases. Biochim Biophys Acta. 2016 July; 1862(7):1267-78; Bach L A, Hale L J. Insulin-like growth factors and kidney disease. Am J Kidney Dis. 2015 February; 65(2):327-36; Mitchell A C, Briquez P S, Hubbell J A, Cochran J R. Engineering growth factors for regenerative medicine applications. Acta Biomater. 2016 January; 30:1-12.) With the dramatic rise in the prevalence of diabetes, age and diabetes-associated non-healing chronic wounds are a critical health problem in the world today. (Demidova-Rice T N, Hamblin M R, Herman I M. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012 July; 25(7):304-14.) Injury typically induces expression of growth factor receptors, and growth factors are involved in all stages of the wound healing process: coagulation, inflammation, formation of granulation tissue and remodeling or scar formation. (Demidova-Rice T N, Hamblin M R, Herman I M. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery. Adv Skin Wound Care. 2012 August; 25(8):349-70; Goldman R. Growth factors and chronic wound healing: past, present, and future. Adv Skin Wound Care. 2004 January-February; 17(1):24-35.) Chronic wounds (vascular ulcers, diabetic ulcers and pressure ulcers) are characterized by decreased density of growth factor receptors and reduced mitogenic response to growth factors. (Demidova-Rice T N et al., supra, Adv Skin Wound Care. 2012 August; 25(8):349-70; Goldman R., supra, Adv Skin Wound Care. 2004 January-February; 17(1):24-35.)
The current paradigm for treating chronic wounds involves debridement (surgical or with debridement agents), control of infection and inflammation (with antibiotics and anti-inflammatory agents), correction of moisture imbalance (with wound dressings) and promotion of re-epithelialization/granulation tissue formation (with growth factors). (Demidova-Rice T N et al., supra, Adv Skin Wound Care. 2012 July; 25(7):304-14.) IGF-1/Insulin are well validated in wound healing both in preclinical and clinical settings, and mouse models of activated PI3K/Akt/mTOR signaling axis show accelerated wound closure. (Mori R, Tanaka K, de Kerckhove M, Okamoto M, Kashiyama K, Tanaka K, Kim S, Kawata T, Komatsu T, Park S, Ikematsu K, Hirano A, Martin P, Shimokawa I. Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring. Am J Pathol. 2014 September; 184(9):2465-79; Lima M H, Caricilli A M, de Abreu L L, Araijo E P, Pelegrinelli F F, Thirone A C, Tsukumo D M, Pessoa A F, dos Santos M F, de Moraes M A, Carvalheira J B, Velloso L A, Saad M J. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial. PLoS One. 2012; 7(5):e3697; Harding K, Aldons P, Edwards H, Stacey M, Finlayson K, Gibb M, Jenkins L, Shooter G, Lonkhuyzen D V, Lynam E, Heinrichs E L, Upton Z. Effectiveness of an acellular synthetic matrix in the treatment of hard-to-heal leg ulcers. Int Wound J. 2014 April; 11(2):129-37; Balaji S, LeSaint M, Bhattacharya S S, Moles C, Dhamija Y, Kidd M, Le L D, King A, Shaaban A, Crombleholme T M, Bollyky P, Keswani S G. Adenoviral-mediated gene transfer of insulin-like growth factor 1 enhances wound healing and induces angiogenesis. J Surg Res. 2014 July; 190(1):367-77; Squarize C H, Castilho R M, Bugge T H, Gutkind J S. Accelerated wound healing by mTOR activation in genetically defined mouse models. PLoS One. 2010 May 13; 5(5):e10643.)
The only FDA approved treatment for chronic wounds is Becaplermin (Regranex) which contains recombinant PDGF and has had limited efficacy. (Eaglstein W H, Kirsner R S, Robson M C. Food and Drug Administration (FDA) drug approval end points for chronic cutaneous ulcer studies. Wound Repair Regen. 2012 November-December; 20(6):793-6.) Recombinant PDGF has several drawbacks as a treatment for chronic wounds, including its short half-life in the protease-rich hostile wound microenvironment and insufficient delivery mechanisms. A need remains for growth factor pathway activators that bypass growth factor receptors (which are downregulated in chronic wounds), have increased stability, and pose no risk for immunogenicity.